Molecular Targets for Neonatal Communicating Hydrocephalus, Putting Shunts out to Pasture?

Monaco, Edward A. III; Friedlander, Robert M.

doi: 10.1227/01.neu.0000428423.76243.df
Science Times

    Hydrocephalus is one of the most common maladies neurosurgeons treat. It can often be one of the most vexing. Typically, the neurosurgeon's role is that of a plumber with the patient requiring at least one, but usually numerous invasive procedures for the placement and revision of ventriculoperitoneal shunts, or endoscopic third ventriculostomy. Despite the frequency with which neurosurgeons encounter hydrocephalus, it remains, arguably, one of the less well understood disease entities. Neonatal forms of hydrocephalus have particularly meaningful consequences because of the duration for which the patient will require a shunt is an entire lifetime. Hypotheses regarding the etiology of neonatal hydrocephalus include increased cerebrospinal fluid (CSF) production, cortical atrophy, and motile cilia impairment. However, recent work by Carter et al at the University of Iowa indicates that neonatal hydrocephalus may be caused by a disruption in the development of certain neural progenitor cells, and that the pathways underlying these events could serve as non-surgical therapeutic targets (Carter CS, Vogel TW, Zhang Q, et al. Abnormal development of NG2+PDGFR-α+ neural progenitor cells leads to neonatal hydrocephalus in a ciliopathy mouse model. Nat Med. 2012; 18(12):1797-1804). Specifically, preventing the loss of a specific population of neural progenitor cells with targeted medical therapies could eventually lead to fewer patients needing shunts.

    On the basis of previous studies showing that cilia dysfunction may have a role in developmental hydrocephalus, Carter et al started with a genetically engineered mouse with intrinsic ciliopathy. Humans with similar mutations can have enlarged ventricles and all mice harboring these Bardet Biedl Syndrome (BBS) mutations develop communicating hydrocephalus. These BBS mutant mice develop communicating hydrocephalus and associated neurological deficits. Ventricular enlargement begins in these mice in the very early postnatal period, even before ependymal motile cilia have matured, suggesting a motile cilia-independent mechanism. To begin to identify the cause of hydrocephalus in the BBS mice, these investigators evaluated the extent of programmed cell death and proliferation in the periventricular regions. Using markers for cell death and proliferation, they demonstrated that mutant mice harbor two-fold increased programmed cell death and a 50% reduction in proliferation in the periventricular regions compared to normal mice. Immunohistochemistry revealed that a specific population of neural progenitor cells possessing neuron-glial antigen 2 and platelet-derived growth factor α (NG2+PDGFR-α+) seemed to be the target of cell death in the mutant mice. Moreover, there were about 50% fewer proliferating NG2+PDGFR-α+ cells in the mutant mice subventricular zones. These experiments suggested that the development of hydrocephalus in the BBS mutant mice was related to the lack of a specific neural progenitor cell population.

    To further isolate the role of the NG2+PDGFR-α+ progenitor cells in hydrocephalus, Carter et al created a conditional knockout of 1 BBS gene in only the PDGFR-α expressing neural progenitor cells. These mice developed hydrocephalus and demonstrated an identical pattern of subventricular zone progenitor cell apoptosis and reduced proliferation as the BBS mice. Ultrastructural analysis of the motile cilia in wild type and conditional knock-out mice revealed no differences, again supporting a motile cilia-independent process. Previous research established that activation the PDGFR-α receptor signaling pathway has an important role in the survival of neural progenitor cells. To test this, these investigators infused PDGFR-α into the ventricles of normal and BBS mutant mice. Normal mice showed profound periventricular proliferation of PDGFR-α+ neural progenitors, while mutant mice did not respond. Taken together, these findings supported the hypothesis that perturbed PDGFR-α signaling in BBS mutant neural progenitors.

    Finally, the investigators sought to rescue BBS mutant mice with perinatal lithium treatments. The rationale behind this treatment lies with the previously established ability of lithium to stimulate downstream elements of the PDGFR-α pathway and promote survival and proliferation of neural progenitor cells. Pregnant BBS mutant and wild-type mice were treated with lithium and histological analysis of the brains of their offspring was performed. Whereas wild-type brains demonstrated no significant changes in ventricular size, mutant mice showed a 50% reduction in the cross-sectional area of the lateral ventricles when compared to sham-treated mutants. Additional immunohistochemical studies identified that although lithium treated BBS mutant mice possess similar numbers of apoptotic cells as sham-treated mice, lithium treatment rescued NG2+PDGFR-α+ neural progenitor proliferation to wild-type levels. Lithium rescued the mutant mice from hydrocephalus by activating components of the PDGFR-α signaling pathway.

    Overall, this intriguing work indicates that some forms of hydrocephalus may be related abnormal development of neural progenitor cells in the subventricular zone. Signaling pathways such as the PDGFRα appear to be fundamental to the survival of a key cell population's survival, the perturbation of which leads to a cilia-independent hydrocephalus. Most interestingly, medical therapy with lithium rescues hydrocephalus, and suggests the possibility that shunts could be avoided in some individuals by targeting downstream elements of the PDGFRα signaling pathway. Certainly, much work remains to establish if such molecular pathways are similarly relevant in humans, but any potential to limit the need for shunting would be welcome.

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